Project Summary F31MH112372-01A1 (PI: Santiago, Adrienne). Early life trauma, particularly during the developmental sensitive period for maternal attachment, is a major, life-long risk factor for psychiatric disorders characterized by heightened fearfulness. The basolateral amygdala (BLA), long known for its integral role in threat response, has been shown to be hyper-responsive following early life trauma. However, the anatomical substrates that mediate increased BLA responsiveness at a synaptic level are unknown. This proposal uses a naturalistic rodent model of maternally-induced early infant trauma to investigate the hypothesis that early life trauma directly alters the inhibitory neurocircuitry mediating BLA-dependent threat response. Maturation of fast-spiking parvalbumin positive inhibitory interneurons (PV cells) plays a major role in defining critical periods of neurodevelopment of sensory cortex. In particular, extracellular molecules form perineuronal nets (PNNs) end the critical period for experience-dependent development of sensory cortex by locking in axo-somatic synapses onto PV somata. Moreover, dissolution of PNNs of mature cortices reinstates plasticity and reopens the experience-dependent sensitive period, thereby once again allowing sensory inputs to drive synaptic rearrangement onto PV cells. While PV cells in the BLA have recently been shown to also play a central role in fear memory in adulthood, its role in innate fear responsivity following early life trauma remains unexplored. Why good maternal care during the post-trauma, pre-weaning period cannot restore normal fear response also remains unknown. This proposal hypothesizes that trauma-induced fear and amygdala hyperactivity are due to PNN locking in an abnormal balance of excitatory-to-inhibitory synapses around the PV cells, thus either weakening the direct PV-->Pyramidal inhibition or abnormally strengthening the PV-->nonPV-->Pyramidal disinhibition, both of which would cause BLA pyramidal cells to become hyperexcitable. This hypothesis leads to the prediction that PNN dissolution during the post-trauma, pre-weaning period will permit healthy maternal care to rewire the fear circuit, thereby normalize the circuitry underlying the traumatized individual?s threat response. To test this hypothesis, Aim 1 will expand the characterization of BLA hyperactivity of traumatized rats, relative to controls? responding to predator odor (innate fear) using telemetry local field potential (LFP) to measure gamma power reflecting PV cell activity. BLA circuitry underlying hyperactivity will be learned through light and electron microscopy to quantify PNN formation and to assess the ratio of inhibitory to excitatory synapses onto PV cells +/- cFos expression, and the extent of PV and non-PV inhibitory contacts onto pyramidal cells +/- cFos expression following threat. Aim 2 will test whether manipulating PV cells optogenetically or dissolving PNNs while providing typical maternal care can normalize traumatized rats? threat response and BLA circuitry (telemetry LFP, LM & EM). The results will highlight the mechanism of infant trauma-induced BLA hyperexcitability and its repair and facilitate our understanding of age-specific treatment for fear disorders.